Cancer treatment is evolving from the empirical administration of chemotherapeutics to the precise deployment of molecularly targeted agents. Targeted therapies that inhibit receptor tyrosine kinases (RTKs) and their downstream signals have shown promising anticancer activity. However, their efficacy in some solid tumours has been modest and/or limited for tumour resistance developed by cancer cells. The Met RTK and its ligand, hepatocyte growth factor/scatter factor (HGF/SF), have become leading candidates for targeted cancer therapies. Inappropriate Met signalling through autocrine, paracrine, amplification, and mutational activation occurs in virtually all types of solid tumours, contributing to one or a combination of proliferative, invasive, survival, or angiogenic cancer phenotypes. Met participate in all stages of malignant progression and represent promising drug targets in a variety of cancer types, including carcinomas, sarcomas, and brain tumours. The key role of Met in cancer has been further elucidated by uncovering its properties to confer resistance to other RTK inhibitors used for therapies. In particular, Met elicits signalling rewiring through “RTK swapping” by substituting ErbBs function, thus conferring resistance to anticancer ErbBs antagonists. For these reasons, Met can be considered as a “nodal signal” not only in cancer malignancy, but also in resistance to therapies. Therefore, agents able to antagonise oncogenic Met are expected to have strong impact in targeted anticancer molecular therapies to impair Met action during tumour formation, aggressiveness acquisition and resistance to therapy.
The absolute requirement for Met under specific physiological and pathological conditions supports the concept that signalling by Met has unique functions in some cancer cells and that inhibiting Met signalling will be particularly effective for therapies of metastatic and/or resistant cancers.
Over the last years, major efforts have been made to identify Met chemical inhibitors containing a large variety of chemical structures [see Cui, J. J. (2007) Expert. Opin. Ther. Patents 17, 1035-1045] and some candidates are currently under clinical evaluation. Many patents and patent applications (more than 80 only in the last 5 years) as well as scientific papers have been published, thus evidencing the relevance of the problem and also the difficulty to find suitable candidates. However, none of these prior art documents disclose compounds having the structure of the compounds of the invention. In particular, Patané et al., [(2008) Biochemical and Biophysical Research Communications 375 (2008) 184-189] disclosed closely related Met-inhibitors. However, the disclosed compounds exhibit in vitro activity in the micromolar range and/or toxicity levels which may prove to be unsufficient.
Close structures have also been published, although not with the disclosure of any c-Met activity. In particular, WO07109120 discloses 4[(imidazo[2,1-b]benzothiazol-2-yl)aniline derivatives, but such derivatives exhibit a specific side chain comprising the —NH—C(═O)—NH— fragment, do not exemplify any amino acid derivative contrary to the compounds of the invention, are specifically active against FLT3, KIT, CSF1R and no information on a possible activity against c-Met is given.
It is thus mandatory to identify new leitmotivs to maximise target inhibition, circumvent resistance acquisition, such as resistance induced by Erbs antagonists, or to improve existing scaffolds either by modelling or by empirical attempts. Moreover, a relatively simple and industrially scalable synthesis is a pre-requisite.
Crystallographic studies have demonstrated that some Met inhibitors, such as “SU11274” [(3Z)—N-(3-Chlorophenyl)-3-({3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrol-2-yl}methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide] and “AM7” [(5-(3-fluoro-4-((6-(methyloxy)-7-((3-(4morpholinyl)propyl)oxy)-4-quinolinyl)oxy)phenyl)-3-methyl-2-(phenylmethyl)-4(3H)-pyrimidinone)], interact within the ATP binding pocket of Met in a distinct manner. This seems to correlate with their differential abilities to inhibit oncogenic mutant forms of Met found in some tumours versus the wild-type form. Thus, Met antagonists, by binding to the receptor in a drastically different manner, can differentially impair activity of Met wild type, oncogenic germ line mutants or with somatic mutations acquired during resistance to treatment. It is suspected that combined treatment with Met inhibitors may be required to successfully shot most of the cancers. However, it is believed that none of the above Met inhibitors have a dual mechanism of action towards Met: impairing Met and downstream signalling.
It is then highly desirable to provide Met inhibitors that: 1) impair Met phosphorylation/activity, 2) act also on signalling downstream of RTKs, 3) counteract other RTKs, such as ErbBs and/or PDGFRs, that together with Met ensure signaling rewiring through RTK swapping, and/or 4) elicit an inhibitory activity at nanomolecular concentration, with a view to treat and/or prevent various forms of cancers or other Met-related diseases. Such agents could be also effective on some type of leukemia characterized by deregulated forms of the Met-related Ron RTK.